The present invention concerns covalent conjugates of topoisomerase I inhibitors (e.g., camptothecins) and topoisomerase II inhibitors (e.g., amsacrine, ellipticines, anthracycline antibiotics, epipodophyllotoxins).
Etoposide is a widely-used antineoplastic agent which inhibits mammalian DNA topoisomerase II isoenzymes. See, F. Drake et al., Biochem. 28:8154 (1989); P. Watt and I. Hickson, Biochem. J. 303:681 (1994); and Y. Pommier, Cancer Chemo. and Pharmac. 32:103 (1993). Various etoposide derivatives have been developed in order to improve antitumor activity, cytotoxicity against drug resistant cells and drug-formulation characteristics including the 4xe2x80x2-O-demethylepipodophyllotoxins bearing C-4xcex2-N-linked substituents. See, Y. Zhang and K. H. Lee, Chin. Pharm. J., 46:319 (1994). The other mammalian DNA topoisomerase, a type I enzyme, is also considered to be a useful therapeutic target. Several selective inhibitors have been identified to date including the antitumor alkaloid, camptothecin, (CPT) and two analogs are currently approved for clinical use in the United States. See, P. Watt and I. Hickson, Biochem. J. 303:681 (1994); and A. Chen and L. Liu, Annu. Rev. Pharmacol. Toxicol. 34:191 (1994). However, not all topoisomerase inhibitors of potential clinical value are topoisomerase-type specific. For example, a 7-H-benzopyrido (4,3-b) indole-derivative (inotoplicine), inhibits topoisomerases I and II simultaneously and can circumvent topoisomerase-mediated mechanisms of drug-resistance. See, B. Podderin et al., Mol. Pharmacol. 44:767 (1993).
All of the above-mentioned compounds share a common inhibitory mechanism which is understood in some depth at the biochemical level. Enzyme inhibition involves the trapping of a putative covalent reaction intermediate called a reversible xe2x80x9ccleavable complexxe2x80x9d. The intracellular lesion, presumably a topoisomerase-DNA-drug ternary complex, ultimately leads to cell death. Although the cytotoxic events depend on the particular type of topoisomerase involved, the precise biochemical pathway(s) to cell killing remains to be defined. See, P. Watt and I. Hickson, Biochem. J. 303:681 (1994); A. Chen and L. Liu, Annu. Rev. Pharmacol. Toxicol. 34:191 (1994); and P. Darpa et al., Cancer Res. 50:6919 (1990).
A first aspect of the present invention is covalent conjugates of topoisomerase I and topoisomerase II inhibitors. Such compounds have a structure according to formula I:
TIxe2x80x94Lxe2x80x94TIIxe2x80x83xe2x80x83(I)
wherein:
TI is a topoisomerase I inhibitor such as a camptothecin group;
TII is a topoisomerase II inhibitor such as an amsacrine, ellipticine, epipodophyllotoxin, anthracycline antibiotic group, or mitoxantrone group; and
L is a linking group.
The compounds of formula I are useful as, among other things, inhibitors of topoisomerase I and topoisomerase II.
The present invention is explained in greater detail in the drawings herein and the specification set forth below.